Prostatic hormonal carcinogenesis is mediated by in situ estrogen production and estrogen receptor alpha signaling
Prostatic hormonal carcinogenesis is mediated by in situ estrogen production and estrogen receptor alpha signaling
复制标题
DOI：
10.1096/fj.07-9526com
复制
发表时间：
2008-05-01
期刊：
影响因子：
4.8
通讯作者：
Risbridger, Gail P.
中科院分区：
文献类型：
--
作者：
Ricke, William A.;McPherson, Stephen J.;Risbridger, Gail P.
最近证实抗雌激素可预防男性前列腺癌（PRCA）。雌二醇（E2）的来源，有助于致癌作用，以及选定的雌激素受体（ER）信号通路，是未知的。为了评价雌激素在肿瘤发生中的作用，我们开发了一种新的PRCA模型，利用睾酮和E2刺激PRCA。为了确定E2的局部原位产生是否影响PRCA的发生率，评价了芳香化酶敲除（ArKO）小鼠。与野生型小鼠相比，ArKO小鼠具有降低的PRCA发生率，这暗示原位产生E2作为PRCA的重要决定因素。为了确定E2介导的应答是否是由于ER α或ER β信号传导，使用ER α敲除（α ERKO）或ER β敲除（β ERKO）小鼠。来自β ERKO小鼠的前列腺经历了与野生型小鼠相似的生物化学和组织学致癌作用，而来自α ERKO小鼠的前列腺保持无病理。这些数据表明，有效预防癌变需要拮抗ER α而不是ER β。该小鼠模型提供了一种检查遗传获得和功能丧失以及确定治疗剂对前列腺癌发生的功效的方法。
It was recently demonstrated that antiestrogens prevented prostate cancer (PRCA) in men. The source of estradiol (E2) that contributes to carcinogenesis, as well as the selected estrogen receptor (ER) signaling pathway, is unknown. To evaluate estrogen's effects in carcinogenesis, we developed a new model of PRCA utilizing testosterone and E2 to stimulate PRCA. To determine whether local in situ production of E2 affected incidence of PRCA, aromatase-knockout (ArKO) mice were evaluated. In contrast to the wildtype mice, ArKO mice had reduced incidences of PRCA, which implicates in situ production of E2 as an important determinant of PRCA. To determine whether E2-mediated responses were due to ER alpha or ER beta signaling, ER alpha-knockout (alpha ERKO) or ER beta-knock-out (beta ERKO) mice were used. Prostates from beta ERKO mice underwent biochemical and histological carcinogenesis similar to wild-type mice, whereas prostates from alpha ERKO mice remained free of pathology. These data suggest that effective prevention of carcinogenesis will require antagonism of ER alpha but not ER beta. This mouse model provides a means to examine genetic gain and loss of function and determine the efficacy of therapeutics on prostatic carcinogenesis.